Differential regulation of two FLNA transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies.

Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG+1 and ATG+82 . A male with CIPO (c.18_19del) exclusively expressed FLNA ATG+82 , implicating the longer protein isoform (ATG+1 ) in smooth muscle development. In contrast, mutations leading to reduction of both isoforms are associated with compound phenotypes affecting the brain, heart, and intestine. RNA-seq data revealed three distinct transcription start sites, two of which produce a protein isoform utilizing ATG+1 while the third utilizes ATG+82 . Transcripts sponsoring translational initiation at ATG+1 predominate in intestinal smooth muscle, and are more abundant compared with the level measured in fibroblasts. Together these observations describe a new mechanism of tissue-specific regulation of FLNA that could reflect the differing mechanical requirements of these cell types during development.

Biallelic mutations in CYP26B1: A differential diagnosis for Pfeiffer and Antley-Bixler syndromes.

Recently, a newly identified autosomal recessive skeletal dysplasia was described characterized by calvarial abnormalities (including cranium bifidum, coronal, and lambdoid synostosis), oligodactyly, femoral bowing, narrow thorax, small pelvic bones, and radiohumeral synostosis. In the two families described, a more severe phenotype led to in utero lethality in three siblings while in a single patient in a second family the phenotype was sufficiently mild to allow survival to 5 months of age. The disorder is caused by biallelic missense mutations in CYP26B1, which encodes for a cytochrome P450 enzyme responsible for the catabolism of retinoic acid in a temporally and spatially restricted fashion during embryonic development. Here, we provide the third family affected by the disorder and the first affected individual to survive beyond infancy. This woman homozygous for c.1303G>A; p.(Gly435Ser) in CYP26B1, which was associated with multisutural synostosis, radiohumeral synostosis, normal bone mineral density, and apparent intellectual disability, a phenotype with significant similarities to Antley-Bixler and Pfeiffer syndromes. © 2016 Wiley Periodicals, Inc.

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A.

Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.